Antibiotics

Medical history is filled with stories of primitive healing customs requiring the use of molds, yeasts and mushrooms, all members of the group of plants known as fungi. It was Louis Pasteur who first established the underlying principle of antibiotics when he concluded that it should be possible to use harmless microbes to fight pathogens, an idea that was developed further by other scientists as the science of bacteriology progressed into the 20th century.

 

In the early 20th century, agricultural bacteriologists were the first to explore the interrelationships among microbes which are basic to the production of antibiotics. In the 1920's, researchers came upon the idea of isolating microbes which can perform a single activity.  Streptomycin was isolated in 1943 and found to be antagonistic to the tuberculosis microbe. It was later administered to guinea pigs infected with tuberculosis and found to be effective. Streptomycin was shown to be effective against tuberculosis in humans in 1945.

 

In the decade that followed the discovery of streptomycin, three so-called broad-spectrum antibiotics were discovered that are available in almost every town today: terramycin, aureomycin andchloromycetin. The antibiotic griseofulvin was discovered to be active against fungal infections; today, it is one of the most common prescriptions written by veterinarians for the treatment of ringworm in animals.

 

Also in the early 20th century, British researcher Alexander Fleming discovered  penicillin from an old culture of the deadly bacterium staphylococcus in which mold had grown. Molds are simple, non-flowering plants belonging to the phylum called fungi. They form minute reproductive particles called spores that float about in the air and often find their way into bacterial cultures where they then grow and multiply.

This pioneering work led other scientists to investigate penicillin. As a result, improved methods were developed for growing the penicillium mold, as well as for harvesting the penicillin. Pure penicillin was eventually isolated and tested in healthy mice, rats, rabbits and cats, none of whom showed ill effects. A method had to be found to manufacture it.

 

The first human trials of penicillin were conducted in 1941. Because there had not been enough animal trials preceding the human tests, the drug was still not effective enough, and most of the patients who volunteered to participate in the first penicillin study did not survive. Once perfected, however, penicillin eventually proved to be effective and safe, and it has since become the most widely-used medicine in the world to fight infectious disease. This drug has few side effects and remains one of the safest medications available.

 

By curing infectious diseases, especially in children and the elderly, penicillin has substantially lengthened overall human life expectancy. Its use in veterinary medicine is also undisputed.

 

Gene Research: The Promise of Genetic Medicine

 

We are in the midst of a major revolution in medicine that is changing the paradigm for health care. The explosions in human genetics and the rapid progress toward the goal of sequencing the human genome will open up unparalleled frontiers for understanding the cellular and molecular changes underlying disease, and with it will come new targets for therapy.

 

The current paradigm for treatment of disease is to see a patient when he or she manifests with signs and symptoms and then to institute appropriate diagnosis and therapy. New advances in genetic medicine will allow the earlier description of the patterns of gene expression which underlie the natural history and process of cellular dysfunction, leading to injury, prior to patients presenting with signs and symptoms. Thus, diseases will be diagnosed much earlier and this will allow preventive therapies to be undertaken to halt the progression of the illness or to slow down its course.

 

Prior to studying patterns of disease in humans, the best way to define the natural history of an illness is to look at its cellular and molecular characteristics in animal models such as in transgenic mice. These models provide unique insights into the cellular mechanisms underlying disease and this information can be rapidly transferred to human diseases with the accompanying improvement in understanding and more rational approach to therapies.

Medical research will be defined as that which was performed before the Human Genome Project and that which occurred after. The field of human molecular genetics is in its earliest stages of development and will reach maturity in the next century. Just as physics heralded the technological advances in the 20^th century, so human genetics will be the catalyst for new insights into disease and new approaches to therapy in the 21^st century. Using these approaches, diseases for which there is currently no rational approach to therapy will be addressed with new approaches based on the insights into the fundamental mechanisms in these diseases. This will lead to new therapies focused directly on the disease mechanism, and is likely to lead to therapies which are more effective and associated with fewer side effects.

 

This is indeed a very exciting time for scientists in this field and for patients suffering from many incurable illnesses who await these discoveries with much hope and also with trepidation.

 

The Heart-Lung Machine

 

For patients whose hearts are in disrepair, cardiac surgery of some form may be the only effective means of correcting the situation. Until the 20th century, successful heart surgery was unthinkable because it was not possible to see inside a heart that was beating and filled with blood. Because of research on dogs and other animals, the 1950's saw an exciting blossoming of advances in cardiac surgery which continues to this day

After decades of work, in 1953 a heart-lung machine was developed that was able to take over temporarily for the heart and lungs. Blood can be re-routed through this machine, bypassing the heart so that surgeons can work inside it.

 

Blood enters the machine from veins that empty into the heart. This blood is returning from its circuit of the body, having given up its oxygen for carbon dioxide. Normally, the heart would pump it to the lungs, where carbon dioxide would be exchanged for fresh oxygen. The heart-lung machine performs this same exchange in an oxygenator. When it has finished this "artificial breathing," it pumps the blood back into the body through an artery. Since its development almost forty years ago, thousands of human and animal hearts have been repaired while this life-saving machine took over for them during surgery.

 

The Cardiac Pacemaker

 

When disease or injury impairs the heart's pacemaker, the heartbeat is disrupted, causing dizziness and sometimes even convulsions or death. A heart can stop beating altogether if the pacemaker fails. Pacemakers are one of the best-known devices for helping this type of an ailing heart. The first pacemaker was a large cart about the size of a wheelbarrow. A smaller pacemaker was developed in the early 1950's in Boston and was worn externally in a shirt pocket. The prevalence of infection as a result of this design required that an implantable pacemaker be developed. Today, programmable pacemakers that last years before needing to be upgraded are used on both humans and animals.

 

The heart valves are like tiny trap doors that connect the different parts of the heart. They are made of flaps of tissue that fit closely together. The valves keep the blood moving in one direction and regulate its flow. In the 1950's, Dr. Michael DeBakey developed artificial veins and arteries, which he perfected and tested in dogs. Artificial heart valves, made from Dacron and other synthetic materials, or pig valves, are now in frequent use to repair defective valves.

 

Monoclonal Antibodies

 

Antibodies (secreted by B lymphocytes) are proteins produced by vertebrate animals as a defense against infection. They are unique among proteins because they are made in millions of different forms, each with different markers that specifically recognize antigens (molecules foreign to the body). In fact, production of an antibody is begun in response to the presence of its complementary antigen.

 

The precise "fit" (specificity) of an antibody for its antigen makes the use of antibodies a very powerful tool for biomedical researchers. Labeled with fluorescent dyes, antibodies can be used to locate the presence of specific molecules in cells. They can also be used to identify specific proteins in a mixture outside the body, making them a useful tool for biochemists.

 

B lymphocytes have a limited life-span in culture. For this reason, individual B lymphocytes from mice immunized with an antigen are fused with cells derived from an "immortal" B lymphocyte tumor. From the resulting mixture of hybrid cells, researchers select hybrids that have the ability to make the antibody and to multiply indefinitely in culture. These so-called hybridomas are propagated as individual clones, each of which provides a permanent and stable source of a single monoclonal antibody. The hybridoma technique allows monoclonal antibodies of a single specificity to be obtained in virtually unlimited amounts.

 

Proteins inside living cells cannot be reached by antibodies added externally because the plasma membrane of the cell is impermeable to large molecules. However, it is possible to introduce antibodies into the cytoplasm of cells by a technique known as microinjection.

 

In principle, monoclonal antibodies can be made against any cellular protein or other macromolecule and can be used to localize and purify the molecule and sometimes even to analyze its function.

Because of their uniform specificity for a given antigen, monoclonal antibodies have enormous advantage over conventional antibodies, which recognize a variety of different markers on an antigen. Because of their ability to detect and localize specific biological molecules, these proteins have become one of the most important research tools in biomedicine.

 

Cyclosporin and Anti-Rejection Drugs

 

Before the success rate in transplant surgery could grow, the body's immune system had to be better understood. The immune system is incapable of differentiating between invasions of the body that are "friendly" (for example, transplantation) and those that are "hostile" (for example, infection). A patient's immune system may thus reject a transplanted organ, just as it would attack deadly bacteria or other antigens. Organ transplants that were successful from a surgical point of view failed because of the immunity factor. Thus, an essential problem in transplantation research was how to treat the body's immune system.

 

The most encouraging development in combating organ rejection was the discovery of a drug called Cyclosporin A in 1972. Cyclosporin has the advantage of suppressing only part of the immune system activated during organ transplantation, and has made it possible for organ transplant patients to enjoy more years of life.

 

Also, as a result of cyclosporin, transplant surgery has progressed and continues to develop into a viable alternative for treating diseased organs.

 

Recently, a new anti-rejection drug called FK-506 has been found. FK-506 is derived from a fungus found in soil samples in Japan. This drug is 50 to 100 times more powerful than cyclosporin, therefore speeding up the patient's recovery. It causes no serious side effects such as kidney damage, elevated blood pressure or mood swings. Its use in the treatment of transplant recipients is already making a difference in their lives.

 

Vaccines

 

The benefits of immunization are readily apparent when the number of cases (in this case, Canadian) are examined before and after the introduction of certain vaccinations*:

* Taken from: Canadian National Report on Immunization, 1998

Affecting Disease	Cases - Pre-Vaccination	Introduction of Vaccine	Cases - Post-Vaccination (1998)
Smallpox	Hundreds of thousands worldwide	1798; global immunization began in 1967	0
Diptheria	9,000 in 1924	1926	1
Whooping Cough	17,000+ annually	1943	7519
Poliomyelitis	11,000 between 1949 and 1954	1955, 1962	0
Measles	300,000 - 400,000 annually	1963	12
Mumps	30,000 in 1940's and 1950's	1969	110

 

Table of Vaccines

 

Cholera Vaccine: While cholera is not currently a life-threatening disease in Canada and the U.S.,  it is still prevalent in parts of the Middle East, Latin America and Asia. A vaccine is available to protect travelers to these parts of the world. Diphtheria Vaccine (DPT vaccine): This is usually given to children combined with tetanus and pertussis (whooping cough) vaccines. Adults generally receive them every 7-10 years. Haemophilus B Vaccine: Children can be protected against the haemophilus Type B bacterium with a vaccine usually given at 2 years of age. This vaccine is particularly recommended for children who attend day-care centers. Hepatitis B Vaccine: Two vaccines are available for people who are at risk of acquiring hepatitis B.  Travelers to a country where hepatitis B is prevalent, health care workers exposed to the hepatitis B virus, and other high-risk individuals have the option of protecting themselves against this disease due to the availability of these vaccines. Influenza Vaccine: While vaccination against influenza is not recommended for the public at large, some people, such as the elderly, are at risk of serious illness if they contract influenza. Measles Vaccine (MMR Vaccine): A live weakened measles vaccine is routinely given to infants, usually in combination with mumps and rubella vaccines (MMR vaccine). Meningococcal Meningitis: While meningitis is relatively uncommon in North America and Europe, the disease is prevalent in regions of Africa and South America. Several vaccines are available to protect travelers to these areas of the world. Mumps Vaccine (MMR Vaccine): Mumps vaccine is given to children in one dose, usually in combination with measles and rubella vaccines (MMR vaccine).

Plague Vaccine: Plague is not a disease found today in the United States, but a vaccine is available to protect travelers to areas of the world where the disease is still prevalent. Pneumococcal Pneumonia Vaccine:While this vaccine is not recommended for the general population, elderly people and other high-risk individuals often choose to become vaccinated. Polio Vaccine: Infants usually receive a live polio vaccine orally at the same time as the DPT vaccine. Because of the polio vaccine, very few cases of this deadly disease are now reported. Rabies Vaccine: While protection against rabies is not necessary for the general population, a vaccine is available for those who travel to or live in areas of the world where rabies is common in domestic animals--areas such as India and parts of South America. Veterinarians also are routinely inoculated against rabies. Rubella Vaccine (MMR Vaccine): This vaccine (also called the Red Measles vaccine) is usually given to infants, in combination with measles and mumps vaccines (MMR vaccine). Although rubella is not a life-threatening disease, if a woman is exposed to it while she is pregnant, her child may be born with severe birth defects. Tetanus Vaccine: Tetanus vaccination is usually given to children as a series of shots and is completed by the time they enter school. It is recommended that adults receive a tetanus/diphtheria booster every 7-10 years. Typhoid Vaccine: While typhoid is uncommon in the west, it is found in many developing countries. A killed vaccine is available to protect travelers to these countries. Yellow Fever Vaccine: Yellow fever is not a threat to the population of North America, but it is widespread in certain areas of Africa and South America. A live virus vaccine is available to protect travelers to these countries.

 

Early Vaccines

 

In the 1800's, outbreaks and epidemics of plague, cholera, smallpox, typhoid fever, tuberculosis,scarlet fever and other dread diseases ravaged entire populations, as they had for centuries.

 

In the 18th century, the average human life expectancy was 31 years. One of the worst killers at this time was smallpox, which killed one out of every ten children under the age of four. In 1796, Edward Jenner, an English country doctor, developed a vaccine against this dread disease that became a model for all later vaccines. Dr. Jenner had observed that dairymaids who suffered from a mild infection called cowpox seemed to be protected from smallpox. Based on this observation, he inoculated people with cowpox and found that it was possible to give them the same immunity as the dairymaids.

 

As a result of Jenner's work, inoculation campaigns against smallpox were launched in North America and Europe. As a result of refinements which made possible the development of a more stable dried vaccine, in 1967 the World Health Organization (WHO) launched a global campaign to eliminate smallpox.  Today smallpox has been eradicated throughout the world.

In the mid-19th century, French chemist Louis Pasteur developed a method for controlling the growth of bacteria, a process which became known in the dairy business as "pasteurization." Pasteur's achievement led to the realization that microorganisms can cause disease, a fact we take for granted in the 20th century.

 

Pasteur became interested in chicken cholera in the mid-19th century. At one point during his study, he infected a group of chickens with an old culture of cholera bacteria, which caused them to develop only a mild case of the disease. When he later infected them with fresh cholera germs, the chickens remained healthy, and Pasteur concluded that they were protected from the disease.

 

Based on this success, he turned his interest to the study of anthrax in cows. Producing a mixture of dead and weakened anthrax bacteria, he successfully protected a group of cows against this deadly disease. He called this mixture a vaccine, after the Latin "vacca" meaning "cow." Following the same formula, in 1885 Pasteur next developed a vaccine for rabies in animals, which he eventually proved was effective for humans as well.

 

Vaccination against diphtheria was made possible in the late 19th century due to work with guinea pigs. Biomedical researchers extracted diphtheria toxin from a broth in which they grew the bacterium. They proved that this toxin was the cause of diphtheria by testing it in guinea pigs, sheep and other animals. Working with guinea pigs infected with diphtheria bacilli, the researchers found a chemical which allowed some of the animals to survive. Blood samples from these immune guinea pigs were extracted, and the serum containing the diphtheria antitoxin was injected into the animals already infected with diphtheria.

Once the antitoxin was proven to help these animals suffering from diphtheria, guinea pigs (and later horses) were used to produce the antitoxin for people suffering from the disease. Diphtheria antitoxin became available for human use in 1895, at a time when the mortality rate for children with this disease was more than 50%.

 

One Canadian physician who practiced north of Toronto in the last century recorded in his daybook that one-quarter of all the children who died in his practice succumbed to Diphtheria. The disease is now extremely rare.

 

These and other early vaccines were breakthroughs that paved the way for all of the immunizations which we now take for granted. Animals were instrumental not only in the investigation of the diseases and the development of vaccines, but in some cases, also in the production of the vaccine itself. Both animals and people now live longer and healthier lives as a result of these vaccines.